蜕膜BDCA-3+树突状细胞扩充及调控母胎免疫耐受的机制研究

The underlying mechanism of unexplained recurrent spontaneous abortion remains unknown. BDCA-3+DCs subset emerges as a natural suppressor of adaptive immune responses. The current study group found the percentage of BDCA-3+DCs in the deciduas was significantly higher than that in the peripheral blood controls, and its percentage in the deciduas from normal pregnancy were significantly higher than that from unexplained recurrent spontaneous abortion. However, the precise mechanisms of decidual BDCA-3+DCs expansion and roles in controlling feto-maternal tolerance in early pregnancy are largely unknown. BDCA-3+DCs were identified to be localized with decidual stromal cell (DSC) by immunohistochemistry. Furthermore, we found that the percentage of BDCA-3+DCs was up-regulated significantly when co-cultured with DSC. Here we plan to investigate the detailed mechanisms of DSC in regulating expansion of decidual BDCA-3+DCs, and the mechanisms of BDCA-3+DCs in promoting Th2 bias was also investigated. Undoubtedly, this study will provide new clue for understanding of immune tolerance necessary for the maintenance of pregnancy, and new thread for diagnosis and therapy of reproductive immune disease such as unexplained recurrent spontaneous abortion and preeclampsia.

不明原因复发性流产(URSA)的病因不明。新近BDCA-3+DCs亚群在免疫应答中所发挥的独特抑制功能备受关注。我们前期研究中一个重要成果是首次发现BDCA-3+DCs占正常早孕蜕膜DCs的多数，且其比例显著高于外周血，而在URSA蜕膜中显著下调。但BDCA-3+DCs在蜕膜部位扩充机制及其在母胎界面的功能尚不清楚。我们前期免疫组化结果显示其与蜕膜基质细胞（DSC）有共定位现象。以往研究证实DSC可与蜕膜中白细胞交互对话，驯导其发生免疫耐受。我们进一步研究发现外周单核细胞来源imDCs与DSC共培养时,BDCA-3+DCs比例显著上调。基于以上，本课题拟探讨DSC诱导母胎界面BDCA-3+DCs扩充的原因及参与的机制，并研究BDCA-3+DCs对T细胞增殖、极化的影响及机制。本项目的完成将对进一步揭示妊娠免疫耐受的机制提供重要理论基础与实验依据，以期为妊娠免疫失衡相关疾病的防治提供新策略。

不明原因复发性流产(URSA)的病因不明。新近BDCA-3+DCs亚群在免疫应答中所发挥的独特抑制功能备受关注。我们前期研究中一个重要成果是首次发现BDCA-3+DCs占正常早孕蜕膜DCs的多数，且其比例显著高于外周血，而在URSA蜕膜中显著下调。但BDCA-3+DCs在蜕膜部位扩充机制及其在母胎界面的功能尚不清楚。本研究完成了URSA患者蜕膜组织及外周血中BDCA-3+DCs的检测。建立了原代DSC分离培养方法、体外CD14+单核细胞诱导分化为BDCA-3+DCs的培养方法，发现DSC可促进 BDCA-3+ DCs 细胞比例上调，进一步机制研究发现VEGF/TGFβ可通过上调BDCA-3 的表达而促进BDCA-3+ DCs的数量扩充。进一步研究BDCA-3+ DCs的免疫调节功能，发现BDCA-3+ DCs 细胞可诱导CD4+ Naïve T 发生Th2 优势应答，而关键性转录因子Foxp3及GATA-3参与这一调控机制。本研究为揭示蜕膜 DCs 免疫耐受功能的发挥提供了新视角，丰富了妊娠植入时母胎免疫耐受建立与维持的机制，同时也将对URSA等病理性妊娠的防治提供新策略。